A subject of the present invention is new derivatives of 2-(iminomethyl)amino-phenyl which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS""s in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
cardiovascular and cerebro-vascular disorders including for example artherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, notably those related with complications of coronary artery bypass grafting, ischemias and thromboses.
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
proliferative and inflammatory diseases such as for example artherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (colitis, Crohn""s disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis).
organ transplants.
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.
cancer.
neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS""s.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS""s (J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).
Furthermore, NO Synthase inhibitors, their use and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties have already been described in previous Patents (respectively U.S. Pat. Nos. 5,081,148; 5,360,925 and an unpublished Patent Application).
A subject of the present invention is the derivatives of 2-(iminomethyl)amino-phenyl, their preparation and their therapeutic use.
The compounds of the invention correspond to general formula (I): 
in which:
A represents a hydrogen atom or:
either a 
xe2x80x83radical in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical, R4 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms;
X represents xe2x80x94Z1xe2x80x94, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94Zxe2x80x21xe2x80x94, xe2x80x94COxe2x80x94NR3xe2x80x94Zxe2x80x21xe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 or a single bond;
Het does not exist or represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substitued by one or more substituents Xxe2x80x2xe2x80x94OR3, Xxe2x80x2xe2x80x94NR3, Xxe2x80x2xe2x80x94Sxe2x80x94R3 and such as for example: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine or 4-aminopiperidine;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Z2xe2x80x94COxe2x80x94, xe2x80x94Z2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Z2xe2x80x94CH2xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals, in which Q represents a single bond, Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Zxe2x80x21, Z2 and Z3 represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z1, Zxe2x80x21, Z2 and Z3 represent xe2x80x94(CH2)mxe2x80x94, m being an integer comprised between 0 and 6;
R6 represents a hydrogen atom or an OH group;
it being understood that when Het is absent, then A is not a hydrogen atom and that when A is hydrogen then Het does not represent a piperidine, pyrrolidine or morpholine radical;
or are salts of the latter.
The compounds of general formula (I) containing an asymmetrical centre are of isomeric form. The racemic and enantiomeric forms of these compounds also form part of this invention.
The compounds of the invention can exist in the state of bases or of addition salts in particular with organic or inorganic acids or with bases, and in particular in the state of hydrates, hydrochlorides, dihydrochlorides, fumarates or hemifumarates.
By linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched alkoxy having from 1 to 6 carbon atoms is meant radicals the alkyl radical of which has the meaning indicated previously. By halogen is meant fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds of general formula (I) are such that they include at least one of the following features:
A represents a 
radical in which R1 and R2 represent, independently, a branched alkyl radical having from 3 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or A represents a 
xe2x80x83radical in which R3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
B represents a thiophene or phenyl radical;
X represents xe2x80x94Z1xe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94NR3xe2x80x94Zxe2x80x21;
Het is absent or represents a piperazine or tetrahydropyridinyl radical;
Y represents xe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94;
R6 represents a hydrogen atom.
A particular subject of the invention is the following compounds of general formula (I), described in the examples (in the form of salts in certain cases):
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;
4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;
3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;
N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;
N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;
N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl }-thiourea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl }-urea;
N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide;
(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamide;
2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;
2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;
2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;
N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;
N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;
N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;
N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;
N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;
N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;
N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;
N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;
N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furan carboxamide;
3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2-imidazolidinedione;
2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;
5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;
2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;
5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridine carboxamide;
N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidine carboxamide;
N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl -4-thiazolecarboxamide;
N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;
methyl 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;
3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;
4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;
1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;
3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;
4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;
4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;
3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;
1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;
1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;
as well as their salts, in particular their hydrochlorides, dihydrochlorides, fumarates or hemi-fumarates.
In a preferential manner, the compounds according to the invention will be one of the following compounds:
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;
3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;
N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;
N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;
N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-{{4-[(2-thienyl(imino)methyl)amino]phenyl}-carbonylamino}-urea;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
Other preferred compounds for the invention will be the following compounds:
4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;
3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
Particularly preferred compounds of the invention will be as follows:
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[4-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidaimide;
N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
More particularly preferred compounds of the invention will be as follows:
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
or a salt of one of the latter, in particular a hydrochloride, dihydrochloride, fumarate or hemi-fumarate of one of the latter.
The invention also offers useful new synthesis intermediates of general formula (xcexa3) 
in which:
A, X, Het, Y and R6 have the same meaning as in general formula (I); and
W represents an amino or nitro radical;
with the exception however of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide.
The invention further comprises a process for preparing a compound of general formula (I) as defined earlier, characterized in that a compound of general formula (xcexa3) 
in which:
A, X, Het, Y and R6 have the same meaning as in general formula (I); and
W represents an amino radical;
is reacted in a lower alcohol, such as methanol, ethanol, isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at a temperature between 20 and 90xc2x0 C., for example at 50xc2x0 C., and for one to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, with a compound of general formula (IV) 
xe2x80x83said compound of general formula (IV) being optionally salified by a mineral acid G, B having the same meaning as in general formula (I) and L representing a leaving group and in particular an alkoxy, thioalkyl, sulphonic acid, halide, aryl alcohol or tosyl radical (other leaving groups well known to a person skilled in the art which can optionally be used for the invention are described in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.
According to a particular variant of the invention, the compounds of the invention correspond to general formula (I)L: 
in which:
A represents:
either a 
xe2x80x83radical in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which R3 has the meaning indicated above
or a 
xe2x80x83radical in which R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms;
X represents xe2x80x94Z1xe2x80x94, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 or a single bond;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals, in which Q represents a single bond, Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Z2 and Z3 represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z1, Z2 and Z3 represent xe2x80x94(CH2)mxe2x80x94, m being an integer comprised between 0 and 6;
R6 represents a hydrogen atom or an OH group;
or are salts of the latter.
There will generally be preferred the compounds of general formula (I)L for which:
X represents a linear or branched alkylene radical having from 1 to 6 carbon atoms and Y represents a piperazine, homopiperazine, 2-methylpipxc3xarazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical; or
X represents xe2x80x94Z1xe2x80x94COxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 and Y represents a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94 radical or xe2x80x94NR3xe2x80x94COxe2x80x94Qxe2x80x2xe2x80x94 radical with Qxe2x80x2=R3xe2x80x94Nxe2x80x94Z3; or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and Y represents xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x3xe2x80x94 with Qxe2x80x3=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, or Y represents xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94 or xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94; or
X represents xe2x80x94Z1xe2x80x94NHxe2x80x94COxe2x80x94 and Y represents a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical; or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 and Y represents xe2x80x94Z2xe2x80x94Qxe2x80x3xe2x80x94 with Qxe2x80x3=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, or Y represents xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94; or
X represents xe2x80x94Z1xe2x80x94 and Y represents xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94; or
X represents xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94 and Y represents xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, or a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94 or xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94 radical; or
X represents a bond and Y represents xe2x80x94Oxe2x80x94Z2xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94Z2xe2x80x94NHxe2x80x94.
Moreover, the X-Y group will preferably be chosen from the following radicals: 
in which T represents a single bond, the xe2x80x94NR3xe2x80x94 radical or the xe2x80x94COxe2x80x94NR3xe2x80x94 radical, or 
in which Rp represents a hydrogen atom or a methyl radical, or 
in which U represents a xe2x80x94Z2, xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Z2xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR3xe2x80x94 radical or an oxygen atom, or 
the Z1, Z2 and R3 radicals having the meaning indicated above.
Finally, there will be particularly preferred for the invention the compounds of general formula (I)L presenting the following characteristics:
either:
A represents: 
X represents xe2x80x94COxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94;
and Y represents an xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94 or piperazine radical, Q representing a single bond or an Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3 radical, and Z2 and Z3 representing independently a bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms and R3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms.
or: R6 is an OH group.
The invention also offers, as new industrial products, the synthetic intermediates of the products of general formula (I)L, namely the products of general formula (II)L: 
in which:
W represents an amino or nitro radical,
A represents:
either a 
radical in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 representing a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which R3 has the meaning indicated above
or a 
xe2x80x83radical in which R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
X represents xe2x80x94Z1xe2x80x94, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 or a single bond;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals, in which Q represents a single bond, Oxe2x80x94Z3, R3xe2x80x94Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Z2 and Z3 represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z1, Z2 and Z3 represent xe2x80x94(CH2)mxe2x80x94, m being an integer comprised between 0 and 6;
R6 represents a hydrogen atom or an OH group;
with the exception however of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;
or the salts of the latter.
Moreover, the invention offers in particular, as new industrial products, the following compounds, which are synthetic intermediates of products of general formula (I):
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;
3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol;
2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;
2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide;
3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
1-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine;
1-[(5 methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine;
2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;
2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)methyl]-urea;
N-[(4-aminophenyl)methyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide;
3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide;
5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;
5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)-carbonylamino]-urea;
N-[(4-aminophenyl)carbonylamino]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[(4-nitrophenyl)methyl]-thiourea;
N-[(4-aminophenyl)methyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-Nxe2x80x2-[2-(4-nitrophenyl)ethyl]-urea;
N-[2-(4-aminophenyl)ethyl]-Nxe2x80x2-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;
1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine;
1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine;
hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;
1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine;
hydrochloride du N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide hydrochloride;
(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-}4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide;
3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide;
2-(4-nitrophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate;
2-(4-aminophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;
or their salts.
Finally, this particular variant of the invention also comprises processes for the preparation of compounds of general formula (I)L as defined above and consisting, for example, of the reaction in a lower alcohol such as methanol, ethanol, isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at a temperature comprised between 20 and 90xc2x0 C., for example at 50xc2x0 C., and for 1 to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, of a compound of general formula (III)L as defined above with a compound of general formula (IV)L 
said compound of general formula (IV)L being optionally salified by a mineral acid G, B having the meaning indicated above and L representing a leaving group and in particular an alkoxy, thioalkyl, sulphonic acid, halide, aryl alcohol or tosyl radical (other leaving groups well known to a person skilled in the art which can optionally be used for the invention are described in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.
Other production processes can be envisaged and can be consulted in the literature (for example: The Chemistry of amidines and imidates, Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley and Sons, 1991).
According to another particular variant of the invention, the compounds of the invention correspond to general formula (I)H: 
in which:
A is a hydrogen atom or an aromatic corresponding to structures: 
in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical, R4 representing an alkyl radical having from 1 to 6 carbon atoms, or 
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a heterocycle with 5 members containing from 1 to 4 heteroatoms chosen from O, S, N and more particularly: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substituted by one or more groups chosen from a linear or branched alkyl radical having from 1 to 6 carbon atoms; an alkoxy radical having from 1 to 6 carbon atoms or a halogen;
X represents xe2x80x94COxe2x80x94N(R3)xe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94COxe2x80x94 or a bond, Xxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Y represents xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94Yxe2x80x2, xe2x80x94Yxe2x80x2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94CO, xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94, Yxe2x80x2xe2x80x94CH2xe2x80x94N(R3)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Sxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94 or a bond, Yxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Het represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substitued by one or more substituents Xxe2x80x2xe2x80x94OR3, Xxe2x80x2xe2x80x94NR3, Xxe2x80x2xe2x80x94Sxe2x80x94R3 and such as for example:
oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,
with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;
it being understood that when A represents a hydrogen atom, Het does not represent a piperidine, pyrrolidine or morpholine radical.
The compounds of general formula (I)H containing one or more asymmetrical centres having isomer forms. The racemics and enantiomers of these compounds are also part of this invention. Similarly, the compounds of the invention can also exist in the state of bases or addition salts with acids.
More particularly the invention relates to the compounds of general formula (I)H in which:
A is a hydrogen atom or an aromatic corresponding to the structure: 
in which R1 and R2 represent, independently a linear or branched alkyl radical having 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
B represents a heterocycle with 5 members containing from 1 to 4 heteroatoms chosen from O, S, N and more particularly: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substitued by one or more groups chosen from a linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or a halogen;
X represents xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94COxe2x80x94 or a bond, Xxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Y represents xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94COxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94 or a bond, Yxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Het represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substituted by one or more substituents Xxe2x80x2xe2x80x94OR3, Xxe2x80x2xe2x80x94NR3, Xxe2x80x2xe2x80x94Sxe2x80x94R3 and such as for example:
oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,
with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine.
Quite particularly the invention relates to the compounds of general formula (I)H in which:
A is a hydrogen atom or an aromatic corresponding to the structure: 
xe2x80x83in which:
R1 and R2 represent, independently a linear or branched alkyl radical having from 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
B represents a thiophene ring, the carbons of which are optionally substituted by one or more groups chosen from a linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or a halogen;
X represents xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94COxe2x80x94 or a bond, Xxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Y represents xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94COxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94 or a bond, Yxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Het represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substituted by one or more substituents Xxe2x80x2xe2x80x94OR3, Xxe2x80x2xe2x80x94NR3, Xxe2x80x2xe2x80x94Sxe2x80x94R3 and such as for example:
oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,
with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine.
Preferred compounds for this variant of the invention include the following compounds (described in the examples):
N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;
N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;
N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;
N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;
N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;
N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;
N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;
N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;
N-(4-}[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;
N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furan carboxamide;
3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione;
2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;
5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;
2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;
5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridine carboxamide;
N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidine carboxamide;
N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}4-thiazolecarboxamide;
N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;
methyl 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;
3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;
4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;
N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;
1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;
3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;
4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;
4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;
3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;
1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;
1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;
1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;
as well as their salts, in particular their hydrochlorides, dihydrochlorides, fumarates or hemi-fumarates.
Preferred compounds for this variant of the invention are the following compounds:
N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide hydroiodide;
N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;
N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide fumarate;
N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide hydrochloride;
N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;
N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide hydroiodide;
N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide fumarate
N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;
N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide fumarate;
N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furan carboxamide hydroiodide;
3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione hydrochloride;
2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-l{imino(2-thienyl)-methylamino]phenyl]-4-thiazolidinone hydrochloride;
5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione fumarate;
2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide hydrochloride;
5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridine carboxamide hydrochloride;
N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidine carboxamide fumarate;
N-[4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)phenyl]-2-thiophenecarboximidamide hydroiodide;
N-[4-hydroxy-3,5-bis-(1,1-dimethyl)ethyl -phenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazole carboxamide hydrochloride;
or their salts or enantiomers.
N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide or its salts is the most preferred compound among the compounds of this variant of the invention.
The invention also offers, as new industrial products, the synthetic intermediates of the products of general formula (I)H, namely the products of general formula (II)H, (III)H, (V)H, (VI)H and (VII)H 
in which
A is a hydrogen atom or an aromatic corresponding to structures: 
xe2x80x83in which:
R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a xe2x80x94COR4 radical R4 representing an alkyl radical having from 1 to 6 carbon atoms, 
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a heterocycle with 5 members containing from 1 to 4 heteroatoms chosen from O, S, N and more particularly: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substituted by one or more groups chosen from a linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or a halogen;
X represents xe2x80x94COxe2x80x94N(R3)xe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94COxe2x80x94 or a bond, Xxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Y represents xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94Yxe2x80x2, xe2x80x94Yxe2x80x2xe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94CO, xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94, Yxe2x80x2xe2x80x94CH2xe2x80x94N(R3)xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Sxe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94, xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94 or a bond, Yxe2x80x2 representing xe2x80x94(CH2)nxe2x80x94 with n an integer from 0 to 6;
Het represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substituted by one or more substituents Xxe2x80x2xe2x80x94OR3, Xxe2x80x2xe2x80x94NR3, Xxe2x80x2xe2x80x94Sxe2x80x94R3 and such as for example:
oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,
with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;
Gp represents a protective group of the amine function preferably cleavable in an anhydrous acid medium, such as for example the carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also the trityl group.
Finally, the invention offers preparation processes for the compounds of general formula (I)H as defined above and consisting of, for example, the reaction in a lower alcohol, such as methanol, ethanol, isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at a temperature between 20 and 90xc2x0 C., for example at 50 xc2x0 C., and for one to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, of a compound of general formula (III)H 
with a compound of general formula (IV)H 
said compound of general formula (IV)H optionally being able to be salified by a mineral acid G, B having the meaning indicated above and L representing a parting group and in particular an alkoxy, thioalkyl , sulphonic acid, halide, aryl alcohol or tosyl radical (other parting groups well-known to a person skilled in the art and being optionally able to be used for the invention are decribed in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.
A subject of the invention is also, as medicaments, the compounds of general formula (I), (I)L or (I)H described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or of their pharmaceutically acceptable salts for producing medicaments intended to inhibit neuronal NO synthase or inductible NO synthase, to inhibit lipidic peroxidation or to provide the double function of NO synthase inhibition and lipidic peroxidation.
More preferably, (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide or a pharmaceutically acceptable salt thereof, will be used in the pharmaceutical compositions of the invention. The same will also be preferred for producing medicaments according to the invention.
In a preferred manner, the compounds of general formula (I), (I)L or (I)H, or their pharmaceutically acceptable salts, and in particular (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide or a pharmaceutically acceptable salt thereof, will be used produce a medicament intended to treat stroke, neurodegenerative diseases or ischemic or hemorragic cardiac or cerebral infarctions, notably those related with complications of coronary artery bypass grafting.
The invention therefore provides a method of treating stroke or neurodegenerative diseases comprising administering to said warm-blooded animal a compound of general formula (I), (I)L or (1)H, or a pharmaceutically acceptable salt thereof, and in particular (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit stroke or neurodegenerative diseases.
The invention also provides a method of preventing or treating ischemic or hemorragic cardiac or cerebral infarctions related with complications of coronary artery bypass grafting in a warm-blooded animal comprising administering to said warm-blooded animal a compound of general formula (I), (I)L or (I)H, or a pharmaceutically acceptable salt thereof, and in particular (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit said ischemic or hemorragic cardiac or cerebral infarctions.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water.
A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc.
The envisaged administration dose for the medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used.
According to the invention, the compounds of general formula (I)L can be prepared by the process described below.
The preparation of the compounds of general formula (I), corresponding to subformulae (I)L and (I)H, is described hereafter.
The compounds of general formula (I)L can be prepared from intermediates of general formula (II)L according to diagram 1.
The reduction of the nitro function of the intermediates of general formula (II)L is generally carried out by catalytic hydrogenation in ethanol, in the presence of Pd/C, except when X=xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 or Y=xe2x80x94Oxe2x80x94CH2xe2x80x94, the nitro group is selectively reduced using, for example, SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842). The reaction is then carried out by heating the mixture to approx. 70xc2x0 C., for at least three hours, in ethyl acetate, sometimes with added ethanol.
The aniline derivatives of general formula (III)L thus obtained can be condensed on derivatives of general formula (IV)L, for example derivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in order to produce final compounds of general formula (I)L (cf. diagram 1). For example, for B=thiophene, the derivatives of general formula (III)L can be condensed on S-methylthiophene thiocarboxamide hydriodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight. 
Preparation of Intermediates of General Formula (II)L 
The intermediates of general formula (II)L can be prepared by different processes depending on the chemical functions which are set up: amines, carboxamides, ureas, thioureas, sulphonamides, aminosulphonylureas, sulphamides, carbamates, ethers, esters, thioethers, acylureas, etc.:
When:
X=linear or branched alkylene radical having from 1 to 6 carbon atoms and
Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The amines of general formula (II)L, diagram 2, in which A, X, Y and R6 are as defined above, can be obtained by nucleophile substitution of the halogenated derivatives of general formula (VI)L by an amine of general formula (VII)L. The reaction is carried out, for example, in DMF in the presence of K2CO3 at 20xc2x0 C. The halogenated derivatives of general formula (VI)L can be accessed, for example, by bromation of the primary alcohols of general formula (V)L using PBr3, at 0xc2x0 C., in anhydrous THF. The alcohols of general formula (V)L which are not commercially available can be prepared according to methods described in the literature (Tetrahedron Lett. (1983), 24, (24), 2495-2496). 
The amines of general formula (VII)L in which Y represents homopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine or more generally xe2x80x94NR3xe2x80x94Z2xe2x80x94NR3xe2x80x94 are synthesized in three stages from the corresponding commercial diamines. The diamines are selectively mono-protected in the form of the carbamate (Synthesis (1984), (12), 1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reaction by nucleophile substitution on a fluoronitrobenzene, in particular 4-fluoronitrobenzene. The amines, previously protected, are released at the last stage, according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition (Wiley-Interscience, 1991)), in order to produce intermediates of general formula (VII)L.
When:
X=xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 and
Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The carboxamides of general formula (II)L, diagram 3, in which A, X, Y and R6 are as defined above, are prepared by condensation of the commercial carboxylic acids of general formula (VIII)L for X=xe2x80x94Z1xe2x80x94COxe2x80x94 and of general formula (IX)L for X=xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 with amines of general formula (VII)L. The non commercial acids can be synthesized according to methods similar to those described in the literature (J. Org. Chem. (1974), 39 (2), 219-222; J. Amer. Chem. Soc. (1957), 79, 5019-5023, and CHIMIA (1991), 45 (4), 121-123 when A represents a 6-alkoxy-2,5,7,8-tetramethylchromane radical). The amines of general formula (VII)L in which Y represents homopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, or more generally xe2x80x94NR3xe2x80x94Z2xe2x80x94NR3xe2x80x94 are prepared according to methods similar to those described in the previous paragraph. The carboxamide bonds are formed under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and
Y=xe2x80x94Z2xe2x80x94Qxe2x80x94
The carboxamides of general formula (II)L in which A, X, Y and R6 are as defined above can also be prepared, as in diagram 4, by peptide condensation of an amine of general formula (X) with a commercial acid of general formula (XI)L. When X=xe2x80x94NR3xe2x80x94COxe2x80x94 and R3=H, the compounds of general formula (X)L are anilines which are obtained by hydrogenation, in the presence of a catalytic quantity of Pd/C, the corresponding nitrobenzene derivatives, themselves synthesized according to a method described in the literature (J. Org. Chem. (1968), 33 (1), 223-226). When X #xe2x80x94NR3xe2x80x94COxe2x80x94 and R3 is a linear or branched alkyl radical having from 1 to 6 carbon atoms, the monoalkylamines can be obtained according to a process described in the literature (U.S. Pat. Nos. 3,208,859 and 2,962,531). The non-commercial carboxylic acids of general formula (XI)L can be accessed using methods described in the literature (Acta Chem. Scand. (1983), 37, 911-916; Synth. Commun. (1986), 16 (4), 479-483; Phophorus, Sulphur Silicon Relat. Elem. (1991), 62, 269-273). 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and
Y=xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94 with Q=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94,
The ureas of general formula (II)L, diagram 5, in which A, X, Y and R6 are as defined above, are prepared by the addition of an amine of general formula (X)L on an isocyanate of general formula (XII)L, (XIII)L or (XIV)L in a solvent such as chloroform at 20xc2x0 C. Synthesis of non-commercial isocyanates of general formula (XII)L is described in the literature (J. Med. Chem. (1992), 35 (21), 3745-3754). The halogenated intermediate ureas (XV)L and (XVII)L are then substituted by a derivative of general formula (XVI)L, in which Q represents Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94, in the presence of a base such as, for example, K2CO3 or NaH in an aprotic solvent such as THF or DMF in order to finally obtain ureas of general formula (II)L. 
When:
X=xe2x80x94Z1xe2x80x94NHxe2x80x94COxe2x80x94 and
Y=piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The ureas of general formula (II)L, diagram 6, in which A, X, Y and R6 are as defined above, are prepared by the addition of an amine of general formula (VII)L, described previously, onto an isocyanate of general formula (XVIII)L in the presence of a base such as diisopropylethylamine.
The isocyanates of general formula (XVIII)L are synthesized from primary amines of general formula (X)L, described previously, triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).
The amines of general formula (VII)L in which Y #xe2x80x94NHxe2x80x94Oxe2x80x94 are prepared according to a method described in the literature (J. Org. Chem. (1984), 49 (8), 1348-1352). 
When:
Xxe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and
Y=xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2xe2x80x94
The aminosulphonylureas of general formula (II)L, diagram 7, in which A, X, Y and R6 are as defined above, are prepared by the addition of amines of general formula (X)L, described previously, onto chlorosulphonylisocyanate (J. Med. Chem. (1996), 39 (6), 1243-1252). The intermediate chlorosulphonylurea (XIX)L is then condensed on the amines of general formula (VII)L, described previously, in order to produce the aminosulphonylureas of general formula (II)L which can optionally be alkylated by a halogenated derivative in the presence of a base such as, for example, NaH in order to produce other derivatives of general formula (II)L. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 and
Y=xe2x80x94Z2xe2x80x94Qxe2x80x94, with Q=Oxe2x80x94Z3xe2x80x94, R3xe2x80x94Nxe2x80x94Z3xe2x80x94 or Sxe2x80x94Z3xe2x80x94,
The sulphonamides of general formula (II)L diagram 8, in which A, X, Y and R6 are as defined above, are prepared by the addition of amines of general formula (X)L, described previously, onto halogenoalkylsulphonyl chlorides of general formula (XX)L. The halogenoalkylsulphonamides of general formula (XXI)L, obtained intermediately, are then condensed on an alcohol, an amine or a thiol of general formula (XVI)L in the presence of a base such as, for example, K2CO3 or NaH, in a polar solvent such as, for example, acetonitrile or DMF. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94SO2xe2x80x94 and
Y=xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94
The sulphamides of general formula (II)L, diagram 9, in which A, X, Y and R6 are as defined above are prepared in three stages from amines of general formula (X)L and chlorosulphonylisocyanate. The reaction of an alcohol, such as tBuOH, on the isocyanate function of chlorosulphonylisocyanate (Tetrahedron Lett. (1991), 32 (45), 6545-6546) leads to an intermediate of chlorosulphonylcarbamate type, which reacts in the presence of an amine of general formula (X)L to produce a derivative of carboxylsulphamide type of general formula (XXII)L. The treatment of this intermediate in a strong acid medium produces the sulphamide derivative of general formula (XXIII)L. Alkylation of the compounds of general formula (XXIII)L by the halogenated derivatives of general formula (XXIV)L in the presence of a base such as, for example, NaH in a polar aprotic solvent allows sulphamide derivatives of general formula (II)L to be obtained. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x80x94 and
Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94
The carbamates of general formula (II)L, diagram 10, in which A, X, Y and R6 are as defined above, are prepared by the reaction of amines of general formula (X)L, described previously, with chloroformate derivatives of general formula (XXV)L prepared according to a method described in the literature (Tetrahedron Lett. (1993), 34 (44), 7129-7132). 
When:
X=xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94 and
Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94
The esters of general formula (II)L, diagram 11, in which A, X, Y and R6 are as defined above, are prepared by the reaction of acids of general formula (VIII)L or (IX)L and alcohols of general formula (XXVI)L in the presence de dicyclohexylcarbodiimide and of a catalytic quantity of 4-dimethylaminopyridine in a solvent such as, for example, THF or DMF at 20xc2x0 C. 
When:
X=xe2x80x94Z1xe2x80x94 and
Y=xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94
The esters of general formula (II)L, diagram 12, in which A, X, Y and R6 are as defined above, can also be prepared by the reaction of acids of general formula (XI)L, described previously, with the alcohols of general formula (V)L under the conditions described previously. 
When:
X=xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94 and
Y=xe2x80x94NHxe2x80x94Z2xe2x80x94Qxe2x80x94, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94
The thioureas of general formula (II)L in which A, X, Y and R6 are as defined above, are prepared from the ureas described previously using Lawesson""s reagent, following an experimental protocol described in the literature (J. Med. Chem. (1995), 38 (18), 3558-3565).
When:
X represents a bond
Y=xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 and
Q=xe2x80x94HNxe2x80x94
The etheroxides or thioetheroxides of general formula (II)L, diagram 13, in which A, X, Y and R6 are as defined above are prepared from dihydroquinones of general formula (XXVII)L (J. Chem. Soc., Perkin Trans. I, (1981), 303-306) or thiophenols of general formula (XXVIII)L (Bio. Med. Chem. Letters, (1993), 3 (12), 2827-2830) and an electrophile (E+) such as, for example, bromoacetonitrile or 4-nitrophenyloxazolinone, in the presence of K2CO3 (J. Heterocyclic Chem., (1994), 31, 1439-1443). The nitriles must be reduced (lithium hydride or catalytic hydrogenation) in order to produce intermediates of general formula (XXIX)L or (XXX)L. The opening of the nitrophenyloxazolinones, accessible by reaction of the corresponding nitroanilines with chloroethylchloroformate as described in the literature (J. Am. Chem. Soc., (1953), 75, 4596), by phenols or thiophenols leads directly to compounds of general formula (XXIX)L or (XXX)L which are then condensed on fluoronitrobenzene in order to produce intermediates of general formula (II)L. 
When:
X represents xe2x80x94Z1xe2x80x94COxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94
Y=xe2x80x94NR3xe2x80x94COxe2x80x94Qxe2x80x94 and
Q=R3xe2x80x94Nxe2x80x94Z3 
The acylureas of general formula (II)L, diagram 14, in which A, X, Y and R6 are as defined above are prepared by condensation of acids of general formula (VIII)L or (IX)L, diagram 3, and ureas of general formula (XXXI)L in the presence of a coupling agent usually used in peptide synthesis, as described previously, in a solvent such as, for example, dichloromethane or DMF. The ureas of general formula (XXXI)L are accessible from isocyanates of general formula (XII)L, diagram 5, according to a method in the literature (J. Chem. Soc., Perkin Trans. 1, (1985), (1), 75-79). 
The compounds of general formula (I)H can be prepared starting from intermediates of general formula (II)H, (III)H or (V)H according to diagram 15. 
The reduction of the nitro function of the intermediates of general formula (II)H is generally carried out by catalytic hydrogenation in ethanol, in the presence of Pd/C, except when the molecules contain an unsaturation or a sulphur atom, this being a poison to the Pd/C. In this case, the nitro group is selectively reduced, for example, by heating the product in solution in ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842) or by using Raney Ni with hydrazine hydrate added to it (Monatshefte fxc3xcr Chemie, (1995), 126, 725-732).
The aniline derivatives of general formula (III)H thus obtained can be condensed on derivatives of general formula (IV)H, for example derivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in order to produce final compounds of general formula (I)H (cf. diagram 15). For example, for B=thiophene, the derivatives of general formula (III)H can be condensed on S-methylethiophene thiocarboxamide hydriodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
The final molecules of general formula (I)H are also accessible through another synthetic route passing through the intermediates of general formula (V)H which carry a heterocyclic amine function protected by a protective group xe2x80x9cGpxe2x80x9d, for example a 2-(trimethylsilyl)ethoxymethyl group (SEM) or by another protective group mentioned in: Protective groups in organic synthesis, 2d ed., (John Wiley and Sons Inc., 1991). The reduction and condensation stages which lead to intermediates (VI)H and (VII)H respectively are carried out under the same conditions as those described previously. The last stage of the synthesis consists in regenerating, for example in an acid medium or in the presence of a fluoride ion, the protected heterocyclic amine function.
Alternatively, the intermediates of general formula (V)H can be converted directly into the intermediate of general formula (II)H by release of the heterocyclic amine by treatment, for example, in an acid medium or in the presence of a fluoride ion.
Preparation of the Compounds of General Formula (II)H, (III)H and (V)H 
The intermediates of general formula (II)H, (III)H and (V)H can be prepared by the different synthetic routes illustrated below.
When:
Het=Imidazole, tetrahydropyridine, thiazolidine, dihydroimidazole-2-one and
Y=xe2x80x94Yxe2x80x2xe2x80x94.
The amines of general formula (II)H, diagram 16, in which A, X, Y and Het are as defined above, can be obtained by nucleophilic substitution of commercial halogenated derivatives of general formula (IX)H by a heterocyclic amine of general formula (VIII)H. The reaction is carried out in acetonitrile, THF or DMF in the presence of a base such as K2CO3 at a temperature varying from 20 to 110xc2x0 C. The synthesis of heterocyclic derivatives of general formula (VIII)H, which are not commercially-available, is described below. 
When:
Het=imidazole, thiazolidine, tetrahydropyridine and
Y=xe2x80x94Yxe2x80x2xe2x80x94.
The heterocyclic amines of general formula (III)H, diagram 17, in which A, X, Y and Het are as defined above, are prepared in two stages starting from the amines of general formula (VIII)H (see below). The mixture of a brominated derivative of general formula (X)H, the synthesis of which is explained in detail below, with an amine of general formula (VIII)H in a solvent such as acetonitrile or DMF in the presence of a base leads to intermediates of general formula (XI)H. The deprotection of the amine function, in an organic acid medium, allows the compounds of general formula (III)H to be obtained. 
When:
Het=thiazolidine and
Y=xe2x80x94COxe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (III)H, diagram 18, in which A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (VIII)H, decribed previously, with the carboxylic acids of general formula (X.2)H. The carboxamide bonds are formed under standard conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). The synthesis of the carboxylic acids of general formula (X.2)H is described below. The intermediates of general formula (XII)H are then deprotected in an acid medium using, for example, trifluroroacetic acid or an organic solution of HCl. 
When:
Het=thiazolidine and
Y=xe2x80x94COxe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (V)H, diagram 19, in which A, X, Y and Het are as defined above, are prepared by condensation of carboxylic acids of general formula (XIII)H with the commercial amines of general formula (XIV)H under standard conditions for peptide synthesis. The synthesis of the carboxylic acids of general formula (XIII)H is described below. 
When:
Het=thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine and
X=xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94.
The carboxamides of general formula (II)H, diagram 20, in which A, X, Y and Het are as defined above, are prepared by condensation of anilines of general formula (XV)H with the carboxylic acids of general formula (XVI)H under standard conditions for peptide condensation. The anilines of general formula (XV)H are obtained by hydrogenation, in the presence of a catalytic quantity of Pd/C, of corresponding nitrobenzene derivatives, themselves synthesized according to a method described in the literature (J. Org. Chem. (1968), 33 (1), 223-226). The acids of general formula (XVI)H, diagram 20, which are not commercially available, are prepared according to methods described in the literature.
The synthesis of pyrroles is described in Chem. Heterocycl. Compd., 1982, 18, 375. The substitued prolines are accessible starting from commercial hydroxyprolines and are prepared according to methods described in J. Org. Chem., 1991, 56, 3009.
The synthesis of the thiazole and tetrahydropyridine derivatives is described below. 
When:
Het=hydantoin and
Y=xe2x80x94Yxe2x80x2xe2x80x94.
The hydantoins of general formula (II)H, diagram 21, in which A, X, Y and Het are as defined above, are prepared in 3 stages starting from the anilines of general formula (XV)H described previously. The substitution of the aniline by ethyl bromoacetate is carried out in the presence of sodium acetate in ethanol at a temperature of approximately 60-70xc2x0 C. The monosubstitution product of general formula (XVII)H is then condensed on an isocyanate of general formula (XVIII)H in an organic solvent such as, for example, dichloromethane, at a temperature of approximately 20xc2x0 C. The cyclization of urea (XIX)H is carried out by heating, at 50xc2x0 C., in ethanol, according to an experimental protocol described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608). The isocyanates of general formula (XVIII)H are synthesised starting from the corresponding commercial primary amines, triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938). 
When:
Het=thiazolidinone and
Y=xe2x80x94Yxe2x80x2xe2x80x94.
The thiazolidinones of general formula (II)H, diagram 22, in which A, X, Y and Het are as defined above, are prepared starting from commercial amines of general formula (XIV)H and aldehydes of general formula (XX)H in the presence of mercaptoacetic acid according to an experimental protocol described in the literature (J. Med. Chem., (1992), 35, 2910-2912). 
When:
Het=hydantoin
X=xe2x80x94CHxe2x95x90and Y=xe2x80x94Yxe2x80x2xe2x80x94.
The hydantoines of general formula (II)H, diagram 23, in which A, X, Y and Het are as defined above, are prepared in 2 stages starting from the isocyanates of general formula (XVIII)H described previously. The reaction of the ethyl ester of sarcosine with the isocyanates of general formula (XVIII)H, is carried out according to an experimental protocol described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608), leads to the formation of the heterocycle of the compounds of general formula (XXI)H. The substitution of the hydantoin is carried out in the presence of a weak base, xcex2-alanine, and an aldehyde of general formula (XX)H according to the experimental conditions described in J. Med. Chem., (1994), 37, 322-328. 
When:
Het=pyrrolidine, thiazolidine
X=xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94 and Y=xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94 or xe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (V)H, diagram 24, in which A, X, Y and Het are as defined above, are prepared by condensation of the anilines of general formula (XV)H, described previously, with the acids of general formula (XXII)H under standard conditions for peptide synthesis. The syntheses of carboxylic acids (XXII)H, which are nont commercially available, are described below. 
When:
Het=tetrahydropyridine and
Y=xe2x80x94COxe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94.
The ureas of general formula (II)H, diagram 25, in which A, X, Y and Het are as defined above, are prepared by condensation of the heterocyclic amines of general formula (VIII)H, described previously, with the isocyanates of general formula (XVIII)H (cf. above) in a solvent such as dichloromethane, at 20xc2x0 C., in the presence of a tertiary amine (e.g. Diisopropylethylamine). 
When:
Het=pyrrolidine, thiazole, thiadiazole and
X=xe2x80x94COxe2x80x94NHxe2x80x94Xxe2x80x2xe2x80x94.
The carboxamides of general formula (II)H, diagram 26, in which A, X, Y and Het are as defined above, are prepared by condensation of commercial carboxylic acids of general formula (XXIII)H with the amines of general formula (XXIV)H under standard conditions for peptide synthesis. The syntheses of the amines of general formula (XXIV)H, which are not commercially available, are described below. 
When:
Het=imidazole, oxazole and thiazole and
Y=xe2x80x94CH(R3)xe2x80x94N(R3)xe2x80x94COxe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (V)H, diagram 27, in which A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV)H with commercial carboxylic acids (or the corresponding acid chlorides) of general formula (XXVI)H under standard conditions for peptide synthesis. The synthesis of the imidazole derivatives of general formula (XXV)H is described below. 
When:
Het=imidazole and
Y=xe2x80x94CH2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94.
The amines of general formula (V)H, diagram 28, in which A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV)H (see below) with the commercial halogenated derivatives of general formula (IX)H under the conditions described previously. 
When:
Het=dihydroimidazole-2-one and
Y=xe2x80x94COxe2x80x94Yxe2x80x2.
The amines of general formula (II)H, diagram 29, in which A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (VIII)H (see below) with the commercial halogenated derivatives of general formula (XXVII)H, for example in an acetonitrile and THF mixture and in the presence of a base such as K2CO3. 
When:
Het=oxazolidinone and
Y=xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94.
The oxazolidinones of general formula (II)H, diagram 30, are prepared starting from the diols of general formula (XXVII)H the synthesis of which is described in the literature (Daumas, M., Tetrahedron, 1992, 48(12), 2373). The formation of carbonates of general formula (XXVIII)H is obtained, for example, in the presence of carbonyl di-imidazole (Kutney, J. P., Synth. Commun., 1975, 5(1), 47) or in the presence of triphosgene at low temperature as described in Synth. Commun., 1994, 24(3), 305. The formation of oxazolidinone occurs during heating of the amines of general formula (XV)H with the carbonates of general formula (XXVIII)H in the presence of an acid catalyst, such as ZnCl2, to xylene reflux in order to eliminate the water formed during the reaction (Laas, H., Synthesis, 1981, 958). 
When:
Het=isoxazoline, isoxazole, oxazole, thiazole and
Y=xe2x80x94Yxe2x80x2xe2x80x94COxe2x80x94NHxe2x80x94Yxe2x80x2xe2x80x94
The carboxamides of general formula (II)H, diagram 3 1, in which A, X, Y and Het are as defined above, can be prepared starting from the commercial amines of general formula (XIV)H and the carboxylic acids of general formula (XXVIII)H by condensation in the presence of isobutyl chloroformate (Org. Prep. Proced. Int., (1975), 7, 215).
The preparation of the oxazoles of general formula (XXVIII)H is carried out according to an experimental protocol described in Tetrahedron Lett., 1994, 35 (13), 2039. Similarly for the synthesis of the thiazoles of general formula (XXVIII)H: J. Med. Chem., 1983, 26, 884. The preparation of the isoxazolines is described below. 
When:
Het=pyrrolidine, piperidine
X=xe2x80x94COxe2x80x94NHxe2x80x94 and
Y=xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (II)H, diagram 32, in which A, X, Y and Het are as defined above, can be prepared by condensation of the commercial carboxylic acids of general formula (XXIII)H with the amines of general formula (XXIX)H under standard conditions for peptide synthesis. The syntheses of amines of general formula (XXIX)H are described below. 
When:
Het=isoxazoline, oxazole, thiazole, imidazole and
Y=xe2x80x94Yxe2x80x2xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94 or xe2x80x94Yxe2x80x2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94.
The etheroxides of general formula (II)H, Diagram 33, in which A, X, Y and Het are as defined above, can be prepared starting from the esters of general formula (XXVIII.4)H, diagram 31.1, by reaction with hydrides, for example LiA1H4, in a solvent such as, for example, anhydrous THF. The primary alcohols thus obtained are then condensed on halogenated derivatives of general formula (IX)H using a base such as for example KOH in an organic medium and in the presence of a phase tranfer catalyst such as for example Aliquat 336.
The primary alcohols (XXXI)H can also be activated in the form of sulphonate derivatives, by tosyl chloride in the presence of pyridine, in order to produce intermediates of general formula (XXXII)H. The condensation of alcohols of general formula (XXII.2)H is then carried out in the presence of a strong base, such as, for example, NaH, in an aporotic solvent (THF or DMF) at a temperature comprised between 20xc2x0 C. and 80xc2x0 C., in order to obtain the ether oxide of general formula (H)H.
Similarly, the amines of general formula (II)H, diagram 33, are obtained by the substitution of the tosylate function of the intermediates of general formula (XXXII)H, obtained in a standard fashion starting from the alcohols of general formula (XXXI)H and tosyl chlosride in the presence of pyridine, by the commercial amines of general formula (XXX)H by reaction in a solvent such as, for example, acetonitrile or DMF, in the presence of a base (K2CO3) at a temperature comprised between 20 and 85xc2x0 C. 
When:
Het=azetidine
X=xe2x80x94COxe2x80x94NHxe2x80x94 and
Y=xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94.
The carboxamides of general formula (III)H, diagram 34, in which A, X, Y and Het are as defined above, can be prepared by condensation of commercial carboxylic acids of general formula (XXIII)H with the amines of general formula (XXXII)H under standard conditions for peptide synthesis. The synthesis of amines of general formula (XXXII)H is descried below. The deprotection of the aniline is carried out by a strong acid such as, for example, trifluoroacetic acid optionally in the presence of triethylsilane. 
When:
Het=azetidine
X=xe2x80x94NHxe2x80x94COxe2x80x94Xxe2x80x2xe2x80x94 and
Y=xe2x80x94Oxe2x80x94Yxe2x80x2xe2x80x94.
The ureas of general formula (III)H, diagram 35, in which A, X, Y and Het are as defined above, can be prepared by the addition of the amines of general formula (XXXII)H on the isocyanates (XXXIV)H obtained from the reaction of the amines of general formula (XV)H with triphosgene in the presence of a tertiary amine such as for example diisopropylethylamine in a neutral solvent such as dichloromethane (J. Org. Chem. (1994), 59 (7), 1937-1938). The ureas of general formula (XXXV)H thus obtained are deprotected by treatment in a strong acid medium as described previously. The synthesis of the amines of general formula (XXXII)H is described below. 
When:
Het=thiazole and
Y=xe2x80x94CH2xe2x80x94N(R3)xe2x80x94Yxe2x80x2xe2x80x94.
The amines of general formula (II)H, diagram 36, in which A, X, Y and Het are as defined above, are prepared by condensation of the amines of general formula (XXV)H (see below) with the commercial halogenated derivatives of general formula (IX)H under the conditions described previously. 
Preparation of Different Synthesis Intermediates
Synthesis of Intermediates (VIII)H 
The syntheses of the intermediates of general formula (VIII)H are illustrated in diagrams 16.1 and 16.2.
The intermediates of general formula (VIII)H, diagram 16.1, can be prepared, for example, in 3 stages starting from 4-imidazole carboxylic acid. The protection of the nitrogen of the heterocycle is carried out using (Boc)2O in the presence of a base such as K2CO3 in DMF. The condensation with the amines of general formula (XV)H (see above) is carried out in a standard fashion under the conditions for peptide synthesis in order to produce the intermediates of general formula (VIII.3)H. The amine of the heterocycle is regenerated by treatment in an acid medium and in particular with trifluoroacetic acid in order to produce the intermediates of general formula (VIII)H. 
The dihydroimidazole-2-ones of general formula (VIII)H, diagram 16.2, can be prepared, for example, in 2 stages starting from the anilines of general formula (XV)H (see above) which are condensed on 2-chloroethyl isocyanate in DMF at 20xc2x0 C. in order to produce the ureas of general formula (VIII.4)H. The cyclization to produce (VIII)H is then carried out by treatment in a basic medium using, for example, tBuOK in DMF. 
Synthesis of Intermediates (X)H 
The intermediates of general formula (X)H, diagram 17.1, can be prepared starting from commercial carboxylic acids of general formula (X.1)H. Protection of the amine function in the form of a carbamate is followed by the selective reduction of the carboxylic acid function by lithium and aluminium hydride in a solvent such as THF, at 20xc2x0 C. Intermediaite (X.3)H is then brominated in the presence of carbon tetrabromide and triphenylphosphine in a solvent such as dichloromethane. 
Synthesis of Intermediates (XIII)H 
The intermediates of general formula (XIII)H, diagram 19.1, can be prepared starting from (R or S) derivatives of thiazolidine carboxylic acids in the presence of (Boc)2O under standard conditions. 
Synthesis of Intermediates (XVI)H 
The intermediates of general formula (XVI)H, diagram 20.1, can be prepared starting from commercial carboxamide derivatives of general formula (XVI.1)H. These carboxamides are treated by a Lawesson reagent in a solvent such as 1,4-dioxane for 2 to 3 hours at a temperature which varies from 25xc2x0 C. to reflux temperature of the mixture. The thiocarboxamides of general formula (XVI.2)H are then treated by ethyl bromopyruvate, at 20xc2x0 C. in DMF according to an experimental protocol described in J. Med. Chem., (1983), 26, 884-891, in order to produce the thiazoles of general formula (XVI.3)H. The saponification of the ester is carried out over 15 hours by aqueous potash in solution in acetone. 
The tetrahydropyridines of general formula (XVI)H, diagram 20.2, can be prepared starting from commercial tetrahydro-4-pyridine carboxylicacid. Esterification is carried out in a standard fashion in the presence of para-toluene sulphonic acid, in methanol, in order to produce to the intermediaire (XVI.4)H which is then condensed on a halogenated derivative of general formula (IX)H under the conditions described previously. The acid of general formula (XVI)H is obtained by saponification in the presence of, for example, LiOH or KOH. 
Synthesis of Intermediates (XXII)H 
The syntheses of intermediates of general formula (XXII)H are described in diagrams 10.1 and 10.2.
The tosyylate function of the (L or D) proline derivatives of general formula (XXII.1)H (Tetrahedron Lett., (1983), 24 (33), 3517-3520), diagram 24.1, is substituted by the alcoholate of the derivaties of general formula (XXII.2)H, generated in situ by a base such as NaH. The substitution is carried out at 20xc2x0 C. in a solvent such as N-methylpyrrolidinone which produces the appropriate inversion of the configuration of the carbon seat of the reaction (Tetrahedron Lett., (1983), 24 (33), 3517-3520). The intermediates of general formula (XXII.3)H thus obtained are then saponified in a standard fashion by alcoholic potash. 
The intermediates of general formula (XXII)H can also be prepared (diagram 24.2) starting from the condensation of cysteine (L or D) on an aldehyde of general formula (XXII.5)H according to an experimental protocol described in the literature (J. Org. Chem., (1957), 22, 943-946). The amine of the heterocycle is then protected in the form of a carbamate in order to produce intermediates of general formula (XXII)H. The aldehydes of general formula (XXII.5)H, which are not commercially available, can be prepared according to J. Chem. Soc., Perkin Trans. I, 1973, 1, 35. 
Synthesis of Intermediates (XXIV)H 
The synthesis of intermediates of general formula (XXIV)H is described in diagram 26.1.
The condensation of the amines (R or S) of general formula (XXIV.1)H, diagram 26.1, on the halogenated derivatives of general formula (IX)H is carried out in the presence of a base such as potassium carbonate in a solvent such as DMF. The condensation product (XXIV.2)H is then deprotected in an acid medium in order to produce intermediates of general formula (XXIV)H. 
Synthesis of Intermediates (XXV)H 
The syntheses of intermediates of general formula (XXV)H are described in diagrams 27.1, 27.2, 27.3 and 27.4.
The imidazoles of general formula (XXV)H, diagram 27.1, can be prepared in 4 stages starting from the commercial compounds (XXV.1)H and (XXV.2)H.
The condensation between the bromoacetophenones of general formula (XXV.1)H and the carboxylic acids of general formula (XXV.2)H is carried out in the presence of Caesium carbonate in DMF. The ketoester obtained (XXV.3)H is cyclized in the presence of 15 equivalents of ammonium acetate by heating in a mixture of xylenes and simultaneous elimination of the water formed during the reaction in order to produce the imidazoles of general formula (XXV.4)H. The nitrogen of the heterocycle is then protected, for example using 2-(trimethylsilyl)ethoxymethyl (SEM) or by another protective group mentioned in: Protective groups in organic synthesis, 2nd ed., (John Wiley and Sons Inc., 1991), in order to produce intermediates of general formula (XXV.5)H. The release of the amine from the chain can be carried out by hydrogenolysis in the presence of Pd/C.
Alternatively, the intermediates of general formula (XXV.4)H can be alkylated in the presence of a base such as, for example, K2CO3, and a reagent such as R3xe2x80x94X in a solvent such as DMF or acetonitrile in order to produce the imidazoles of general formula (XXV.6)H. Deprotection of the side chain, as described previously, allows the intermediates of general formula (XXV)H to be accessed. 
The intermediates of general formula (XXV)H containing an oxazole, thiazole or an imidazole are also accessible via other synthetic routes such as that described in Bioorg. and Med. Chem. Lett., 1993, 3, 915 or Tetrahedron Lett., 1993, 34, 1901. The intermediates of general formula (XXV.7)H thus obtained can be modified, diagram 27.2, by saponification followed by decarboxylation, for example thermic, in order to produce disubstituted heterocycles of general formula (XXV.9)H. Release of the amine from the side chain, as described previously, allows the intermediates of general formula (XXV)H to be accessed. 
Alternatively, the carboxylic function of the heterocycles of general formula (XXV.7)H, can be reduced, for example by NaBH4, in order to produce alcoholic derivatives of general formula (XXV.10)H, diagram 27.3, which can be alkylated in the presence of R3xe2x80x94X and a base such as K2CO3 in a solvent such as acetonitrile or DMF. Release of the amine from the side chain, as described previously, allows the intermediates of general formula (XXV)H to be accessed. 
The thiazoles of general formula (XXV)H, diagram 27.4, can also be prepared in 4 stages starting from commercial sarcosinamide hydrochloride. The amine is first protected in a standard fashion in the form of tBu carbamate and the carboxamide function is converted into thiocarboxamide in the presence of Lawesson reagent. The formation of the thiazole ring is carried out by the reaction of thiocarboxamide with the intermediate of general formula (XXV.1)H according to an experimental protocol described in the literature (J. Org. Chem., (1995), 60, 5638-5642). The amine function is regenerated by treatment with the intermediate of general formula (XXV.12)H in a strong acid medium such as, for example, trifluoroacetic acid. 
Synthesis of Intermediates (XXVIII)H 
The isoxazolines and isoxazoles of general formula (XXVIII)H, Diagram 31.1, are prepared by reaction of commercial aldehydes of general formula (XX)H with hydroxylamine hydrochloride. The oxime of general formula (XXVIII.1)H thus obtained is activated in the form of the oxime chloride, of general formula (XXVIII.2)H, by reaction with N-chlorosuccinimide in DMF before reacting with the esters of general formula (XXVIII.3)H in order to produce isoxazoline derivatives or with the esters of general formula (XXVIII.4)H in order to produce isoxazole derivatives according to an experimental protocol described in the literature (Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084). Saponification of the isoxazolines or isoxazoles of general formula (XXVIII.5)H is then carried out in a standard fashion under the conditions described previously.
The unsaturated esters of general formula (XXVIII.3)H and (XXVIII.4)H, which are not commercially available, can be prepared according to methods described in the literature (J. Med. Chem., 1987, 30, 193; J. Org. Chem., 1980, 45, 5017). 
Synthesis of Intermediates (XXIX)H 
The syntheses of intermediates of general formula (XXIX)H are described in diagrams 32.1, 32.2, 32.3 and 32.4
The intermediates of general formula (XXIX)H can be prepared, diagram 32.1, starting from the intermediates of general formula (XXII.3)H, described previously, by treatment in a strong acid medium to regenerate the heterocyclic amine function. The selective reduction of the carboxylic function in the presence of, for example, sodium borohydride in a solvent such as, for example, anhydrous THF, allows the intermediate of general formula (XXIX)H carrying a primary alcohol function to be obtained without touching the nitro group (Rao, A. V. R., J. Chem. Soc. Chem. Commun., 1992, 11, 859). 
The intermediates of general formula (XXIX)H can also be prepared, diagram 32.2, starting from intermediates of general formula (XXIX.1)H (R or S) the preparation of which is similar to that of the compounds of general formula (XXII.1)H. Condensation of the alcoholic derivatives of general formula (XXII.2)H on the intermediates of general formula (XXIX.1)H is also described above. Release of the heterocyclic amine is carried out in the presence of an organic solution of a strong acid, for example, trifluoroacetic acid. 
The amines of general formula (XXIX)H, diagram 32.3, are also accessible starting from the substitution of tosylated derivatives of general formula (XXIX.1)H by the commercial amines of general formula (XXX)H. Detachment of the carbamate function from the intermediates of general formula (XXIX.3)H is carried out as described previously. 
The intermediates of general formula (XXIX)H can also be prepared, diagram 32.4, by reaction of the halogenated derivatives of general formula (IX)H with an alcohol of general formula (XXIX.4)H in the presence of a base such as for example tBuOxe2x88x92K+ in an anhydrous solvent such as THF. The intermediate of general formula (XXIX.5)H thus obtained is then deprotected in a strong acid medium (HCl or TFA). 
Synthesis of Intermediates (XXXII)H 
The intermediates of general formula (XXXII)H can be prepared, diagram 34.1, by reaction of the halogenated derivatives of general formula (IX)H with commercial 1-(diphenylmethyl)-3-hydroxyazetidine (XXXII.1)H in the presence of a base such as for example NaH in an anhydrous solvent such as THF. In this case, the nitro group of the intermediate of general formula (XXXII.2)H is reduced in the presence of SnCl2, as described previously, in order to produce the intermediate of general formula (XXXII.3)H the amine of which is then protected in the form of a tButyl carbamate. The detachment of the diphenylmethyl protective group is then carried out in a standard fashion by hydrogenolysis in the presence of Pd(OH)2 in order to produce the intermediate of general formula (XXXII)H. 
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which the invention belongs. Similarly, all publications, Patent Applications, Patents and other references mentioned here are incorporated by way of reference.